Project Highlights

MoA：

1. CCR8 is a G protein-coupled receptors (GPCRs) that is expressed on Th2 cells, monocytes and NK cells. CCR8 was also expressed in Treg cells, and was highly expressed in tumor-infiltrating Tregcells, and was lower in thymocyte, spleen and peripheral blood. CCR8 participates in the development of various tumors and mediates tumor immunity through the interaction with its ligand. The high specific expression of CCR8 on Treg at tumor indicates that CCR8 is an excellent biomarker of Treg cells for tumor and a potential tumor immune target.

2. CCR8and Treg cell-mediated immunosuppression CCR8+regulatory T cells (Treg cells) are the driving factors of immunosuppression. CCR8 is an immunosuppressive receptor that mediates the immune escape of tumor cells. CCL1 can attract FOXp3+CCR8+Treg cells to infiltrate into tumor tissue through the interaction with its ligand CCR8, and present immunosuppressive function. At the same time, CCL1 can induce the up-regulation of CCR8 expression on the surface of FOXp3+Treg cells and induce Ca2+ flow, which cause the up-regulation of stat3 dependent Foxp3, CD39, IL-10 and granulozyme B expression, thus enhancing the immunosuppressive activity of these tumor-infiltrating Treg cells; CCR8 was highly expressed on FOXP3+Tregs in tumor tissue of patients, but significantly decreased in blood. This is different from targets such as CCR4, CTLA-4 and CD25. The specific expression of CCR8 on tumor site Treg cells makes the development of CCR8 targeted monoclonal antibody drugs is expected to specifically inhibit the function of tumor site Treg and help cancer treatment.

Excellent preclinical results:

1. FACS test showed that the affinity with hCCR8 and cynoCCR8 was higher than that of the positive drug (Shionogi S-531011), and it did not bind with hCCR4 cells.

2. The antibody can effectively block the interaction between CCL1/hCCR8, and strong ADCC and ADCP activities were observed in vitro.

3. The antibody maintained high stability in accelerated test, low pH condition and human plasma.

4. It showed excellent tumor inhibition effect in vivo in hCCR8 mice.

Research progress:

Ongoing Preclinical research

The targeted therapy of CCR8 humanized antibody has the potential to treat multiple solid tumors.

Effectively reduce the immunosuppressive effect of Treg cells in tumor microenvironment.

Shown good target affinity and stability in vitro.

Shown good tumor inhibition ability in vivo.